The overall goal of this research is to define the mechanisms and consequences of estrogens actions on the forebrain, which we will address in two specific aims. The first aim is to determine the cellular consequences of estrogen-mediated alterations in the ratio of neurotrophin receptors. In the adult forebrain, estrogen increases trk receptors and decreases p75, resulting in a favorable trk/p75 ratio, while in the reproductively senescent forebrain, estrogen replacement, paradoxically, results in an unfavorable trk/p75 ratio. While both neurotrophin receptors stimulate distinct and overlapping signaling pathways, the trks typically promote cell survival, while p75 may stimulate either cell survival or cell death. Here, our in vivo models will be used to assess how estrogen mediated changes in trk/p75 ratios will affect down-stream neurotrophin signaling and, consequently, cell fate, when challenged, in vivo, with neurotrophin stimulation or injury. The second aim is to test the hypothesis that expression/activation of the alpha form of the estrogen receptor (ER-alpha) is detrimental to cell health. Two estrogen receptors have been identified, although the specific contribution of each receptor to neural function is not clearly defined. Recent observations indicate that high ER-alpha expression is associated with decreased estrogen responsiveness on measures such as neurotrophin expression and cell survival. Estrogen receptor specific ligands, in conjunction with ex vivo and in vitro models, will be used to determine the contribution of each estrogen receptor to neurotrophin expression, signal transduction and cell death. These studies will also employ DNA microarray analysis, with the eventual goal of developing strategic gene arrays to facilitate rapid detection of estrogen-mediated cellular changes and to discriminate between the actions of receptor specific ligands. In view of the recent conflicting evidence regarding estrogen use and Alzheimer's disease, understanding the biology of estrogens actions are more critical now than ever. Moreover, identifying hormone-stimulated pathways that initiate cell-degenerative events will be increasingly important to the development of target and receptor specific estrogenic compounds.